Method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine

A technology of cyanotetrahydropyrrole and formamidotetrahydropyrrole is applied in the field of preparing -N-chloroacetyl-2-cyanotetrahydropyrrole, and can solve the problem of difficult industrialized production, high cost, low yield, etc. problem, to achieve the effect of less difficulty in operation, improved yield and low cost

CN102491928AInactive Publication Date: 2012-06-13LINHAI TIANYU PHARMA
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2012-06-13
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention provides a method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine, which belongs to the technical field of chemical medicine midbody preparation methods. The preparation method comprises the steps: (1) L-proline and thionyl chloride generate acylation reaction to obtain L-proline chloride; (2) the L-proline chloride and ammonia water generate reaction to produce L-proline amide; (3) the L-proline amide and chloroacetyl chloride generate reaction to obtain (2S)-N-chloracetyl-2-carbamoyl pyrrole; and (4) (2S)-N-chloracetyl-2-carbamoyl pyrrolidine and phosphorus oxychloride generate dehydration reaction under low temperature condition to obtain the (2S)-N-chloracetyl-2-cyano-group pyrrolidine. The method has the advantages of saving material cost, being simple in technological process, moderate in reaction condition, low in operation difficulty, convenient in aftertreatment, stable in quality and suitable for mass industrial production, having operability, and improving yield of prepared products by a large margin.
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Description

technical field

[0001] The invention belongs to the technical field of preparation methods of pharmaceutical intermediates, and in particular relates to a method for preparing (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole. Background technique

[0002] (2S)-N-Chloroacetyl-2-cyanotetrahydropyrrole is the key intermediate of vildagliptin, a new hypoglycemic drug. Currently adopted synthetic methods require relatively high production equipment, high cost, and lower yields of (2S)-N-chloroacetyl-2-cyanotetrahydropyrrole, domestic related literature reports, published Research on the synthesis of dipeptidyl peptidase-IV inhibitor vildagliptin, which uses L-proline to acetylate first, then uses expensive DCC, and dehydrates with phosphorus oxychloride to obtain (2S) -N-chloroacetyl-2-cyanotetrahydropyrrole, its yield is very low cost and too expensive, it is difficult to realize industrial production; In addition, foreign related documents US6166063, WO0034241, Beilstein Journal o...

Examples

Embodiment 1

[0025] Embodiment 1: a kind of preparation (2S)- N -Chloroacetyl-2-cyanotetrahydropyrrole method

[0026] (1) Add 10g of L-proline and 50ml of dichloromethane into a 100ml four-neck flask, start stirring, cool down to 0-5°C, maintain this temperature and slowly add 20.7g of thionyl chloride dropwise, and heat up to Reflux and keep warm for 1 hour. After the reaction is complete, the solvent is evaporated to dryness under reduced pressure at 30° C. to obtain 15 g of L-prolyl chloride.

[0027] (2) Slowly add the above-mentioned 15gL-prolyl chloride dropwise to 100g 20% ​​ammonia water at 0-5°C, and react at -10°C-40°C for 1-10 hours. After the reaction is complete, dichloromethane 100ml*6 was extracted six times, the organic layers were combined, dried, suction filtered, and the filtrate was precipitated under reduced pressure at 30°C to dryness to obtain 8g of L-prolinamide, Mp: 96~98°C, [α]D 20 -106 0 (c=2C 2 h 5 Oh)

[0028] (3) Add 100ml of tetrahydrofuran to 8gL-pr...

Embodiment 2

[0033] Embodiment 2: a kind of preparation (2S)- N -Chloroacetyl-2-cyanotetrahydropyrrole method

[0034] The process of this embodiment is the same as that of Example 1, and the difference is that the heat preservation and reflux in the step of preparing prolyl chloride in the step (1) is changed from 1 hour to 10 hours, and the yield can still be 15gL-prolyl chloride, and thus As a raw material does not affect the next step of the reaction.

Embodiment 3

[0035] Embodiment 3: A kind of preparation (2S)- N -Chloroacetyl-2-cyanotetrahydropyrrole method

[0036] The process of this embodiment is the same as that of Example 1, the difference being that the reaction temperature of adding prolyl chloride dropwise to ammonia water in step (2) is changed to 0°C~40°C, the reaction time is changed to 3~6 hours, and the The rate can still achieve 8gL-prolineamide and it will not affect the next step reaction as a raw material.